1. Field of the Invention
The present invention relates to a process for resolving enantiomerically impure citalopram into an enriched enantiomeric citalopram compound, and to compounds useful therein.
2. Description of the Prior Art
Citalopram, chemically 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, is a pharmaceutically-active compound that acts as a highly-selective serotonin reuptake inhibitor (SSRI). Citalopram has been disclosed in U.S. Pat. No. 4,136,193. The chemical structure can be represented as follows:

Citalopram has one assymetric carbon (carbon 1 of the dihydroisobenzofuran ring), and thus it may exist in two enantiomeric forms: (S)-citalopram and (R)-citalopram. The pharmacological activity lies predominantly in its (S)-enantiomer, while the (R)-enantiomer is approximately 30-fold less potent.
Racemic citalopram hydrobromide salt has been marketed as an antidepressant for humans under the brand name Celexa® (Forrest Laboratories Inc., St. Louis, Mo. USA). While citalopram was originally marketed as a racemic compound, it has been proposed to administer the substantially pure (S)-enantiomer of citalopram to human patients in order to have fewer side effects. Accordingly, a pharmaceutical formulation comprising the substantially pure (S)-enantiomer of citalopram (generically referred to as escitalopram) has been recently marketed under the brand name Lexapro® (Forrest Laboratories Inc.). The active compound in this medicament is escitalopram oxalate (1:1).
Various production processes yielding substantially enantiomerically pure (S)-citalopram have been reported, including the chromatographic separation of the enantiomers of citalopram (see, e.g., WO 03/006449) and the resolution of citalopram derivatives (see, e.g., Elati et al. (Organic Process Research and Development 11 (2), 289-292, 2007)). U.S. Pat. No. 4,943,590 (reissued as U.S. Pat. No. Re 34,712 and corresponding to EP 0 347 066 B1) reports that previous attempts to crystallize diastereomeric salts of citalopram enantiomers have failed.
WO 03/006449 discloses a chromatographic process for the separation of the enantiomers of citalopram (or an intermediate in the production of citalopram) using a chiral stationary phase. The process is generally economically disadvantageous on an industrial scale due to the high cost of the stationary phase and the low capacity thereof.
Elati et al. reports that “[p]rompted by the ready accessibility of [racemic] citalopram [ ], initially we focused on development of a diastereomeric salt resolution process for [racemic citalopram]” (Organic Process Research and Development 11 (2), at 289-90). Acknowledging the failure reported by U.S. Pat. No. 4,943,590, Elati et al. discloses that “[o]f the many resoluting agents screened, use of (-)-DPTTA [O,O′-di-p-toluoyl-(2R,3R)-tartaric acid], though found to be useful, in our hands proved to be unsatisfactory for an industrial-scale application due to low yields and multiple crystallizations” (Organic Process Research and Development 11 (2), at 290)(citation omitted). As a result, Elati et al. turned to the resolution of a citalopram derivative (as opposed to citalopram itself), which “led to an efficient, scalable, and economic synthesis of [escitalopram].” Also see WO 2005/047274 A1.
In view of the difficulties encountered with resolving citalopram directly using standard crystallization techniques, it would be desirable to have an effective and relatively simple or inexpensive process for resolving racemic citalopram into its enantiomers in high purity, especially a crystallization route suitable for use on an industrial scale.